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neurogenetative disease

Rick M Tankard, Mark F Bennett, Peter Degorski, Martin B Delatycki, Paul J Lockhart, Melanie Bahlo
Repeat expansions cause more than 30 inherited disorders, predominantly neurogenetic. These can present with overlapping clinical phenotypes, making molecular diagnosis challenging. Single-gene or small-panel PCR-based methods can help to identify the precise genetic cause, but they can be slow and costly and often yield no result. Researchers are increasingly performing genomic analysis via whole-exome and whole-genome sequencing (WES and WGS) to diagnose genetic disorders. However, until recently, analysis protocols could not identify repeat expansions in these datasets...
November 20, 2018: American Journal of Human Genetics
Jorge Sepulcre, Michel J Grothe, Federico d'Oleire Uquillas, Laura Ortiz-Terán, Ibai Diez, Hyun-Sik Yang, Heidi I L Jacobs, Bernard J Hanseeuw, Quanzheng Li, Georges El-Fakhri, Reisa A Sperling, Keith A Johnson
Tau and amyloid beta (Aβ) proteins accumulate along neuronal circuits in Alzheimer's disease. Unraveling the genetic background for the regional vulnerability of these proteinopathies can help in understanding the mechanisms of pathology progression. To that end, we developed a novel graph theory approach and used it to investigate the intersection of longitudinal Aβ and tau positron emission tomography imaging of healthy adult individuals and the genetic transcriptome of the Allen Human Brain Atlas. We identified distinctive pathways for tau and Aβ accumulation, of which the tau pathways correlated with cognitive levels...
October 29, 2018: Nature Medicine
Zachary D Wallen, Honglei Chen, Erin M Hill-Burns, Stewart A Factor, Cyrus P Zabetian, Haydeh Payami
Objective: To identify modifiers of age at diagnosis of Parkinson disease (PD). Methods: Genome-wide association study (GWAS) included 1,950 individuals with PD from the NeuroGenetics Research Consortium (NGRC) study. Replication was conducted in the Parkinson's, Genes and Environment study, including 209 prevalent (PAGEP ) and 517 incident (PAGEI ) PD cases. Cox regression was used to test association with age at diagnosis. Individuals without neurologic disease were used to rule out confounding...
October 2018: Neurology. Genetics
Xiaowei W Su, Zachary Simmons
Recent advances in the genetics of neurologic diseases coupled with improvements in sensitivity and specificity are making genetic testing an increasingly important part of diagnosis and management for neurologists. However, the complex nature of genetic testing, the nuances of multiple result types, and the short- and long-term consequences of genetic diagnoses raise important ethical issues for the clinician. Neurologists must balance the ethical principles of beneficence and nonmaleficence, on the one hand, with patient autonomy on the other hand, when ordering such tests by facilitating shared decision making, carrying out their fiduciary responsibilities to patients, and ensuring that patients have adequate counseling to make informed decisions...
October 2018: Seminars in Neurology
W B V R Pinto, F G M Naylor, M A T Chieia, P V S de Souza, A S B Oliveira
Facial-onset sensory and motor neuronopathy (FOSMN) syndrome represents a rare, slowly progressive, lower motor neuron disease with sensory compromise, involving mainly the face, bulbar region and upper limbs. However, non-motor symptoms and neurogenetic studies have rarely been evaluated in large case series. In the present study, 10 unrelated Brazilian patients with FOSMN syndrome underwent extensive clinical, laboratory, neurophysiological and neurogenetic assessment. Median age at symptom onset was 52.1 years, and men and women were equally affected...
October 4, 2018: Revue Neurologique
Burt M Sharp, Hao Chen
The single most preventable cause of disease, disability, and death in the United States is tobacco use. Decades of study show that the risk of becoming addicted to smoked cigarettes varies greatly amongst individuals and is heritable, yet environmental factors are also important contributors. In this review, we consider a wide range of methodologies and key published reports that have defined the inheritance of different stages of nicotine-dependent smoking behavior, including preference, initiation, regular use, withdrawal and dependence as well as cessation and relapse...
September 26, 2018: European Journal of Neuroscience
Florentine Radelfahr, Thomas Klopstock
Mitochondrial diseases (MD) represent a heterogenous group of disorders and syndromes caused either by mutations of the mitochondrial DNA (mtDNA) or the nuclear DNA (nDNA). They belong to the most frequent neurogenetic diseases. The spectrum of clinical manifestations is very broad ranging from mild subclinical presentations to rapidly progressive debilitating conditions with reduced life expectancy. Mitochondrial dysfunction can affect any organ of the body; the clinical presentation is often most severe in tissues with high energy demands...
September 2018: Fortschritte der Neurologie-Psychiatrie
Georgios Koutsis, Marianthi Breza, Georgios Velonakis, John Tzartos, Dimitrios Kasselimis, Chrisoula Kartanou, Efstratios Karavasilis, Dimitrios Tzanetakos, Maria Anagnostouli, Elisavet Andreadou, Maria-Eleftheria Evangelopoulos, Constantinos Kilidireas, Constantin Potagas, Marios Panas, Georgia Karadima
OBJECTIVE: X linked Charcot-Marie-Tooth disease (CMTX) is a hereditary neuropathy caused by mutations in GJB1 coding for connexin-32, a gap junction protein expressed in Schwann cells, but also found in oligodendrocytes. Four patients with CMTX developing central nervous system (CNS) demyelination compatible with multiple sclerosis (MS) have been individually published. We presently sought to systematically investigate the relationship between CMTX and MS. METHODS: Over 20 years, 70 consecutive patients (36 men) with GJB1 mutations were identified at our Neurogenetics Unit, Athens, Greece, and assessed for clinical features suggestive of MS...
September 8, 2018: Journal of Neurology, Neurosurgery, and Psychiatry
Vanessa L Merker, Annie Dai, Heather B Radtke, Pamela Knight, Justin T Jordan, Scott R Plotkin
BACKGROUND: Our primary aim was to assess the ability of a non-profit foundation-sponsored clinic network to facilitate access to specialized care for patients with neurofibromatoses (NF), a group of neurogenetic disorders including NF1, NF2, and schwannomatosis (SWN). Our secondary aim was to identify how our findings in NF could be applied more broadly to other rare diseases. METHODS: We retrospectively reviewed aggregate data on patient volume reported by specialty NF clinics in a nonprofit network from 2008 to 2015...
August 29, 2018: BMC Health Services Research
Angeliki Vgontzas, William Renthal
Genetic variation can directly cause or increase susceptibility to neurological diseases. An explosion of new genetic technologies has enabled the characterization of specific genes responsible for many neurological diseases and has provided fundamentally new insight into their pathophysiology. These advancements, along with recent breakthroughs in gene therapy, are beginning to result in the translation of an individual's genetic sequence into targeted treatment strategies. This review aims to introduce key genetic concepts and to illustrate how these principles apply in cases of rare, single-gene neurological diseases as well as more common, polygenic diseases that are encountered frequently in clinical practice...
August 8, 2018: American Journal of Medicine
Ce Kang, Christina Liang, Kate E Ahmad, Yufan Gu, Sue-Faye Siow, James G Colebatch, Scott Whyte, Karl Ng, Philip D Cremer, Alastair J Corbett, Ryan L Davis, Tony Roscioli, Mark J Cowley, Jin-Sung Park, Carolyn M Sue, Kishore R Kumar
Genetic testing strategies such as next-generation sequencing (NGS) panels and whole genome sequencing (WGS) can be applied to the hereditary cerebellar ataxias (HCAs), but their exact role in the diagnostic pathway is unclear. We aim to determine the yield from genetic testing strategies and the genetic and phenotypic spectrum of HCA in Australia by analysing real-world data. We performed a retrospective review on 87 HCA cases referred to the Neurogenetics Clinic at the Royal North Shore Hospital, Sydney, Australia...
August 4, 2018: Cerebellum
Alessandra Rufa, Aasef G Shaikh
No abstract text is available yet for this article.
2018: Frontiers in Neurology
Sainath Raman, Latifa Chentouf, Catherine DeVile, Mark J Peters, Shamima Rahman
BACKGROUND: Mitochondrial and neurogenetic diseases can present diagnostic challenges. We investigated if near infrared spectroscopy with the vascular occlusion test is able to differentiate between children with mitochondrial disease and children with neurogenetic disease or healthy controls. METHODS: Prospective observational study conducted in a tertiary children's hospital. RESULTS: Forty-three children with mitochondrial disease (including both genetically confirmed primary mitochondrial disease and cases with biochemical evidence of mitochondrial dysfunction), 19 children with non-mitochondrial neurogenetic disease and 13 healthy controls were recruited...
2018: PloS One
William D Walters, Adolfo D Garnica, Gerald Bradley Schaefer
We present the case of a young woman with worsening attacks of muscle pain and rhabdomyolysis beginning at age 14. Initial metabolic testing and electromyography revealed findings of a nonspecific myopathy. Diagnostic options were discussed among the members of a neurogenetics clinic team. Whole-exome sequencing was selected as a first tier test. This testing revealed a known disease causing mutation in the PYGM gene consistent with McArdle disease. We discuss the decision to use whole-exome sequencing in diagnostics and the rationale for making this our choice as a first-level test modality...
July 2018: Seminars in Pediatric Neurology
D Heidelberg, S Ronsin, F Bonneville, S Hannoun, C Tilikete, F Cotton
Ataxia is a neurodegenerative disease resulting from brainstem, cerebellar, and/or spinocerebellar tracts impairments. Symptoms onset could vary widely from childhood to late-adulthood. Autosomal cerebellar ataxias are considered as one of the most complex group in neurogenetics. In addition to their genetic heterogeneity, there is an important phenotypic variability in the expression of cerebellar impairment, complicating the genetic mutation research. A pattern recognition approach using brain MRI measures of atrophy, hyperintensities and iron-induced hypointensity of the dentate nuclei, could be therefore helpful in guiding genetic research...
September 2018: Journal of Neuroradiology. Journal de Neuroradiologie
Jeremiah Hadwen, Sarah Schock, Alan Mears, Robert Yang, Philippe Charron, Liying Zhang, Hualin S Xi, Alex MacKenzie
Rare monogenic diseases affect millions worldwide; although over 4500 rare disease genotypes are known, disease-modifying drugs are available for only 5% of them. The sheer number of these conditions combined with their rarity precludes traditional costly drug discovery programs. An economically viable alternative is to repurpose established drugs for rare diseases. Many genetic diseases result from increased or decreased protein activity and identification of clinically approved drugs which moderate this pathogenic dosage holds therapeutic potential...
September 15, 2018: Human Molecular Genetics
Paulo Victor Sgobbi Souza, Bruno Mattos Lombardi Badia, Luiz Henrique Libardi Silva, Carlos Alberto Castro Teixeira, Daniel Delgado Seneor, Vitor Dias Gomes Barrios Marin, Igor Braga Farias, Renan Braido Dias, Acary Souza Bulle Oliveira, Wladimir Bocca Vieira Rezende Pinto
BACKGROUND: Hypomyelinating leukodystrophies represent an expanding group of neurogenetic disorders characterized primarily by central nervous system hypomyelination and variable neurological and non-neurological involvement. Hypomyelinating disorders have been rarely associated with gonadal dysfunction, being mainly represented by hypogonadotrophic hypogonadism in 4H syndrome. WT1 gene-associated disorders are classically associated with complex phenotypes including early carcinogenic risk for gonadoblastoma and Wilms' tumor, chronic renal failure, nephrotic syndrome and sex developmental disorders in intersex disorders and ambiguous genitalia...
July 15, 2018: Journal of the Neurological Sciences
John P Grady, Sarah J Pickett, Yi Shiau Ng, Charlotte L Alston, Emma L Blakely, Steven A Hardy, Catherine L Feeney, Alexandra A Bright, Andrew M Schaefer, Gráinne S Gorman, Richard Jq McNally, Robert W Taylor, Doug M Turnbull, Robert McFarland
Mitochondrial disease associated with the pathogenic m.3243A>G variant is a common, clinically heterogeneous, neurogenetic disorder. Using multiple linear regression and linear mixed modelling, we evaluated which commonly assayed tissue (blood N  = 231, urine N  = 235, skeletal muscle N  = 77) represents the m.3243A>G mutation load and mitochondrial DNA (mtDNA) copy number most strongly associated with disease burden and progression. m.3243A>G levels are correlated in blood, muscle and urine ( R 2  = 0...
June 2018: EMBO Molecular Medicine
Cornelia Volz, Myriam Mirza, Thomas Langmann, Herbert Jägle
Neuronal ceroid lipofuscinosis (NCL) is the most common group of neurogenetic storage diseases typically beginning in childhood. The juvenile form (JNCL), also known as Batten disease, is the most common form. Vision-related problems are often an early sign, appearing prior to motor and mental deficits. We have previously investigated disease progression with age in the Cln3 Δex7/8 KI mouse model for JNCL and showed a decline of visual acuity and a predominant decline of the inner retinal function in mice, similar to human disease...
2018: Advances in Experimental Medicine and Biology
James J Fink, Eric S Levine
Animal models of neurodevelopmental disorders have provided invaluable insights into the molecular-, cellular-, and circuit-level defects associated with a plethora of genetic disruptions. In many cases, these deficits have been linked to changes in disease-relevant behaviors, but very few of these findings have been translated to treatments for human disease. This may be due to significant species differences and the difficulty in modeling disorders that involve deletion or duplication of multiple genes. The identification of primary underlying pathophysiology in these models is confounded by the accumulation of secondary disease phenotypes in the mature nervous system, as well as potential compensatory mechanisms...
2018: Frontiers in Neurology
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